This application is a continuation of U.S. application Ser. No. 09/244,340 filed Feb. 4, 1999, now abandoned, which is a continuation-in-part of U.S. patent application Ser. No. 09/001647, filed Dec. 31, 1997, now U.S. Pat. No. 6,321,164, which is a continuation-in-part of U.S. patent application Ser. No. 08/859,773 to Givens et al. filed May 21, 1997, now U.S. Pat. No. 6,101,449, issued Aug. 8, 2000, which is a continuation of U.S. patent application Ser. No. 08/477,839 to Givens et al. filed Jun. 7, 1995, now U.S. Pat. No. 5,708,591, issued Jan. 13, 1998, all of which are incorporated by reference. U.S. Pat. No. 5,646,046 to Fischer et al. is also incorporated herein by reference. This application is further related to the following publications, the subject matter of each also being incorporated herein by reference:
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Blood clots are the end product of a complex chain reaction where proteins form an enzyme cascade acting as a biologic amplification system. This system enables relatively few molecules of initiator products to induce sequential activation of a series of inactive proteins, known as factors, culminating in the production of the fibrin clot. Mathematical models of the kinetics of the cascade's pathways have been previously proposed.
In B. Pohl, C. Beringer, M. Bomhard, F. Keller, The Quick Machine—a Mathematical Model for the Extrinsic Activation of Coagulation, Haemostasis, 24, 325-337 (1994), a dynamic model of the extrinsic coagulation cascade was described where data were collected for 20 samples using quick percent, activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, factor (F) II, FV, FVII, FX, anti-thrombin III (ATIII), and factor degradation product (FDP) assays. These data were used as input to the model and the predictive output compared to actual recovered prothrombin time (PT) screening assay results. The model accurately predicted the PT result in only 11 of 20 cases. These coagulation cascade models demonstrate: (1) the complexity of the clot formation process, and (2) the difficulty in associating PT clot times alone with specific conditions.
Thrombosis and hemostasis testing is the in vitro study of the ability of blood to form clots and to break clots in vivo. Coagulation (hemostasis) assays began as manual methods where clot formation was observed in a test tube either by tilting the tube or removing fibrin strands by a wire loop. The goal was to determine if a patient's blood sample would clot after certain materials were added. It was later determined that the amount of time from initiation of the reaction to the point of clot formation in vitro is related to congenital disorders, acquired disorders, and therapeutic monitoring. In order to remove the inherent variability associated with the subjective endpoint determinations of manual techniques, instrumentation has been developed to measure clot time, based on (1) electromechanical properties, (2) clot elasticity, (3) light scattering, (4) fibrin adhesion, and (5) impedance. For light scattering methods, data is gathered that represents the transmission of light through the specimen as a function of time (an optical time-dependent measurement profile).
Two assays, the PT and APTT, are widely used to screen for abnormalities in the coagulation system, although several other screening assays can be used, e.g. protein C, fibrinogen, protein S and/or thrombin time. If screening assays show an abnormal result, one or several additional tests are needed to isolate the exact source of the abnormality. The PT and APTT assays rely primarily upon measurement of time required for clot time, although some variations of the PT also use the amplitude of the change in optical signal in estimating fibrinogen concentration.
Blood coagulation is affected by administration of drugs, in addition to the vast array of internal factors and proteins that normally influence clot formation. For example, heparin is a widely-used therapeutic drug that is used to prevent thrombosis following surgery or under other conditions, or is used to combat existing thrombosis. The administration of heparin is typically monitored using the APTT assay, which gives a prolonged clot time in the presence of heparin. Clot times for PT assays are affected to a much smaller degree. Since a number of other plasma abnormalities may also cause prolonged APTT results, the ability to discriminate between these effectors from screening assay results may be clinically significant.
Using a sigmoidal curve fit to a profile, P. Baumann, T. Jurgensen, C. Heuck, Computerized Analysis of the In Vitro Activation of the Plasmatic Clotting System, Haemostasis, 19, 309-321 (1989) showed that a ratio of two coefficients was unique for a select group of blood factor deficiencies when fibrinogen was artificially maintained by addition of exogenous fibrinogen to a fixed concentration, and that same ratio also correlates heparin to FII deficiency and FXa deficiencies. However, the requirement for artificially fixed fibrinogen makes this approach inappropriate for analysis of clinical specimens. The present invention makes it possible to predict haemostatic dysfunction for clinical samples from a time-dependent measurement profile without artificial manipulation of samples.
The present invention was conceived of and developed for predicting haemostatic dysfunction in an unknown sample based on one or more time-dependent measurement profiles, such as optical time-dependent measurement profiles, where one or more predictor variables are provided which define characteristics of profile, and where in turn a model is derived that represents the relationship between the haemostatic dysfunction and the one or more predictor variables (so as to, in turn, utilize this model to predict the haemostatic dysfunction in the unknown sample). In addition, the present invention is directed to predicting the presence of Disseminated Intravascular Coagulation in a patient based on a time-dependent profile, such as an optical transmission profile, from a clotting assay run on the patient's blood or plasma sample.